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Identification of New KRAS G12D Inhibitors through Computer-Aided Drug Discovery Methods
Apoorva M Kulkarni1, Vikas Kumar1, Shraddha Parate2
1Department of Bio and Medical Big Data (BK4 Program), Division of Life Science, Research Institute of Natural Science, Gyeongsang National University, 501 Jinju-daero, Jinju 52828, Korea.
Abstract:
Owing to several mutations, the oncogene Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is activated in the majority of cancers, and targeting it has been pharmacologically challenging. In this study, using an in silico approach comprised of pharmacophore modeling, molecular docking, and molecular dynamics simulations, potential KRAS G12D inhibitors were investigated. A ligand-based common feature pharmacophore model was generated to identify the framework necessary for effective KRAS inhibition. The chemical features in the selected pharmacophore model comprised two hydrogen bond donors, one hydrogen bond acceptor, two aromatic rings and one hydrophobic feature. This model was used for screening in excess of 214,000 compounds from InterBioScreen (IBS) and ZINC databases. Eighteen compounds from the IBS and ten from the ZINC database mapped onto the pharmacophore model and were subjected to molecular docking. Molecular docking results highlighted a higher affinity of four hit compounds towards KRAS G12D in comparison to the reference inhibitor, BI-2852. Sequential molecular dynamics (MD) simulation studies revealed all four hit compounds them possess higher KRAS G12D binding free energy and demonstrate stable polar interaction with key residues. Further, Principal Component Analysis (PCA) analysis of the hit compounds in complex with KRAS G12D also indicated stability. Overall, the research undertaken provides strong support for further in vitro testing of these newly identified KRAS G12D inhibitors, particularly Hit1 and Hit2.
Insights
Researchers identified novel drug candidates targeting the KRAS G12D mutation, a common driver in many cancers. Computational methods revealed four promising inhibitors with strong binding affinity and stability, warranting further investigation.
Area of Science:
- Oncology
- Computational Chemistry
- Drug Discovery
Background:
- The Kirsten rat sarcoma 2 viral oncogene homolog (KRAS) is frequently mutated in various cancers, posing a significant therapeutic challenge.
- Targeting KRAS mutations, particularly KRAS G12D, is crucial for developing effective cancer treatments.
Purpose of the Study:
- To identify novel small-molecule inhibitors for the KRAS G12D oncoprotein using in silico approaches.
- To evaluate the binding affinity and stability of potential inhibitors through computational simulations.
Main Methods:
- Generation of a ligand-based common feature pharmacophore model for KRAS inhibition.
- Screening of large compound databases (InterBioScreen and ZINC) against the pharmacophore model.
- Molecular docking, molecular dynamics (MD) simulations, and Principal Component Analysis (PCA) to assess binding and stability.
Main Results:
- A pharmacophore model with specific chemical features (H-bond donors/acceptor, aromatic/hydrophobic groups) was established.
- Four hit compounds exhibited higher binding affinity to KRAS G12D than the reference inhibitor BI-2852.
- MD simulations and PCA confirmed the stable binding and interactions of the identified hit compounds with KRAS G12D.
Conclusions:
- The study successfully identified four potent KRAS G12D inhibitors through computational screening and validation.
- Hit1 and Hit2 compounds demonstrate significant potential for further in vitro testing and development as cancer therapeutics.
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